1H-imidazole derivatives having cb1 agonistic, cb1 partial agonistic or cb1 antagonistic activity

ABSTRACT

The present invention relates to a group of novel 1H-imidazole derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component. These 1H-imidazole derivatives are potent cannabinoid-CB1 receptor agonists, partial agonists or antagonists, useful for the treatment of psychiatric and neurological disorders, as well as and other diseases involving cannabinoid neurotransmission. The compounds have the general formula (I) wherein R and R1-R4 have the meanings given in the specification.

[0001] The present invention relates to a group of novel 1H-imidazolederivatives, to methods for the preparation of these compounds, and topharmaceutical compositions containing one or more of these compounds asan active component.

[0002] These 1H-imidazole derivatives are potent cannabinoid-CB₁receptor agonists, partial agonists or antagonists, useful for thetreatment of psychiatric and neurological disorders, as well as andother diseases involving cannabinoid neurotransmission.

[0003] Cannabinoids are present in the Indian hemp Cannabis sativa andhave been used as medicinal agents for centuries (Mechoulam, R. andFeigenbaum, J. J. Prog. Med. Chem. 1987, 24, 159). However, only withinthe past ten years the research in the cannabinoid area has revealedpivotal information on cannabinoid receptors and their (endogenous)agonists and antagonists. The discovery and the subsequent cloning oftwo different subtypes of cannabinoid receptors (CB₁ and CB₂) stimulatedthe search for novel cannabinoid receptor antagonists (Munro, S. et al.,Nature 1993, 365, 61. Matsuda, L. A. and Bonner, T. I. CannabinoidReceptors, Pertwee, R. G. Ed. 1995, 117, Academic Press, London). Inaddition, pharmaceutical companies became interested in the developmentof cannabinoid drugs for the treatment of diseases connected withdisorders of the cannabinoid system (Consroe, P. Neurobiology of Disease1998, 5, 534. Pop, E. Curr. Opin. In CPNS Investigational Drugs 1999, 1,587. Greenberg, D. A. Drug News Perspect. 1999, 12, 458. Pertwee, R. G.,Progress in Neurobiology 2001, 63, 569). Hitherto, several CB, receptorantagonists are known. Sanofi disclosed their diarylpyrazole congenersas selective CB, receptor antagonists. A representative example isSR-141716A (Dutta, A. K. et al., Med. Chem. Res. 1994, 5, 54. Lan, R. etal., J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E. M. et al., CNSDrug Rev. 1999, 5, 43). CP-272871 is a pyrazole derivative, likeSR141716A, but less potent and less CB, receptor subtype-selective thanSR141716A (Meschler, J. P. et al., Biochem. Pharmacol. 2000, 60, 1315).Aminoalkylindoles have been dis-closed as CB₁ receptor antagonists. Arepresentative example is Iodopravadoline (AM-630), which was introducedin 1995.

[0004] AM-630 is a moderately active CB, receptor antagonist, in someassays behaving as a weak partial agonist (Hosohata, K. et al., Life Sc.1997, 61, PL115). Researchers from Eli Lilly described aryl-aroylsubstituted benzofurans as selective CB, receptor antagonists (e.g.LY-320135) (Felder, C. C. et al., J. Pharmacol. Exp. Ther. 1998, 284,291). 3-Alkyl-5,5′-diphenylimidazolidine-diones were described ascannabinoid receptor ligands, which were indicated to be cannabinoidantagonists (Kanyonyo, M. et al., Biorg. Med. Chem. Lett. 1999, 9,2233). Aventis Pharma claimed diarylmethyleneazetidine analogs as CB₁receptor antagonists (Mignani, S. et al., Patent FR 2783246, 2000; Chem.Abstr 2000, 132, 236982). Tricyclic pyrazoles were claimed bySanofi-Synthelabo as CB₁ antagonists (Barth, F. et al. Patent WO0132663, 2001; Chem. Abstr. 2001, 134, 340504). Interestingly, many CB₁receptor antagonists have been reported to behave as inverse agonists invitro (Landsman, R. S. et al., Eur. J. Pharmacol. 1997, 334, R₁).Pyrazole cannabinoids have also been reported as CB, receptor partialagonists showing in vivo cannabimimetic effects (Wiley, J. L. et al., J.Pharmacol. Exp. Ther. 2001, 296, 1013). A number of classes of CB,receptor agonists are known such as for example the classicalcannabinoids (e.g. Δ⁹-THC), non-classical cannabinoids,aminoalkylindoles and eicosanoids (e.g. anandamide). Reviews provide anice overview of the cannabinoid research area (Mechoulam, R. et al.,Prog. Med. Chem. 1998, 35, 199. Lambert, D. M. Curr. Med. Chem. 1999, 6,635. Mechoulam, R. et al., Eur. J. Pharmacol. 1998, 359, 1. Williamson,E. M. and Evans, F. J. Drugs 2000, 60, 1303. Pertwee, R. G. AddidtionBiology 2000, 5, 37. Robson, P. Br. J. Psychiatry 2001, 178, 107.Pertwee, R. G. Prog. Neurobiol. 2001, 63, 569. Goya, P. and Jagerovic,N. Exp. Opin. Ther. Patents 2000, 10, 1529. Pertwee, R. G. Gut 2001, 48,859).

[0005] It has now surprisingly been found that the novel 1H-imidazolederivatives of the formula (I), prodrugs thereof and salts thereof, arepotent agonists, partial agonists or antagonists on cannabinoid-CB,receptors

[0006] wherein

[0007] R represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, whichgroups may be substituted with 1, 2, 3 or 4 substituents Y, which can bethe same or different, from the group C₁₋₃-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, mono- or dialkyl (C₁₋₂)-amino, mono- or dialkyl (C₁₂)-amido,(C₁₋₃)-alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl, or Rrepresents naphtyl, with the proviso that when R is 4-pyridinyl, R₄represents a halogen atom or a cyano, carbamoyl, formyl, acetyl,trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl,methylsulfanyl or branched or unbranched C₁₋₄ alkyl group, which C₁₋₄alkyl group may be substituted with 1-3 fluoro atoms or with a bromo,chloro, iodo, cyano or hydroxy group,

[0008] R₁ represents phenyl or pyridinyl, which groups may besubstituted with 1-4 substituents Y, which can be the same or different,wherein Y has the above mentioned meaning, or R₁ represents pyrimidinyl,pyrazinyl, pyridazinyl or triazinyl, which groups may be substitutedwith 1-2 substituents Y, which can be the same or different or R₁represents a five-membered aromatic heterocyclic ring having one or twoheteroatoms from the group (N, O, S), which heteroatoms can be the sameor different, which five-membered aromatic heterocyclic ring may besubstituted with 1-2 substituents Y, which can be the same or differentor R₁ represents naphtyl,

[0009] R₂ represents H, branched or unbranched C₁₋₈ alkyl, C₃₋₈cycloalkyl, C₃₋₈ alkenyl, C₅₋₈ cycloalkenyl which groups may contain asulfur, oxygen or nitrogen atom,

[0010] R₃ represents branched or unbranched C₂₋₈ alkyl, C₁₋₈ alkoxy,C₅₋₈ cycloalkyloxy, C₃₋₈ cycloalkyl, C₅₋₁₀ bicycloalkyl, C₆₋₁₀tricycloalkyl, C₃₋₈ alkenyl, C₅₋₈ cycloalkenyl, which groups mayoptionally contain one or more heteroatoms from the group (O, N, S) andwhich groups may be substituted with a hydroxy group or 1-2 C₁₋₃ alkylgroups or 1-3 fluoro atoms, or R₃ represents a benzyl or phenethyl groupwhich aromatic rings may be substituted with 1-5 substituents Z, whichcan be the same or different, from the group C₁₋₃-alkyl or alkoxy,hydroxy, halogen, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, nitro, amino, mono- or dialkyl (C₁₂)-amino, mono- ordialkyl (C₁₋₂)-amido, (C₁₋₃)-alkylsulfonyl, dimethyl-sulfamido,C₁₋₃-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano,carbamoyl, sulfamoyl and acetyl, or R₃ represents a phenyl or pyridinylgroup, which groups are substituted with 1-4 substituents Z, wherein Zhas the meaning as indicated above,

[0011] or R₃ represents a pyridinyl group, or R₃ represents a phenylgroup, with the proviso that R₄ represents a halogen atom or a cyano,carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl,sulfamoyl, methanesulfonyl, methylsulfanyl or C₁₋₄ alkyl group, whichC₁₋₄ alkyl group may be substituted with 1-3 fluoro atoms or with abromo, chloro, iodo, cyano or hydroxy group, or R₃ represents a groupNR₅Rr with the proviso that R₂ represents a hydrogen atom or a methylgroup, wherein

[0012] R₅ and R₆ are the same or different and represent branched orunbranched C₁₋₄ alkyl, or R₅ and R₆— together with the nitrogen atom towhich they are bonded—form a saturated or unsaturated, monocyclic orbicyclic heterocyclic group having 4 to 10 ring atoms which heterocyclicgroup contains one or two heteroatoms from the group (N, O, S), whichheteroatoms can be the same or different, which heterocyclic group maybe substituted with a C₁₋₃ alkyl group or a hydroxy group, or R₂ and R₃—together with the nitrogen atom to which they are bonded—form asaturated or unsaturated heterocyclic group having 4 to 10 ring atomswhich heterocyclic group contains one or two heteroatoms from the group(N, O, S), which heteroatoms can be the same or different, whichheterocyclic group may be substituted with a C₁₋₃ alkyl group or ahydroxy group,

[0013] R₄ represents a hydrogen or halogen atom or a cyano, carbamoyl,formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl,methanesulfonyl, methylsulfanyl or branched or unbranched C₁₋₄ alkylgroup, which C₁₋₄ alkyl group may be substituted with 1-3 fluoro atomsor with a bromo, chloro, iodo, cyano or a hydroxy group,

[0014] Due to the potent CB₁ agonistic, partial agonistic orantagonistic activity the compounds according to the invention aresuitable for use in the treatment of psychiatric disorders such aspsychosis, anxiety, depression, attention deficits, memory disorders,cognitive disorders, appetite disorders, obesity, addiction, appetence,drug dependence and neurological disorders such as neurodegenerativedisorders, dementia, dystonia, muscle spasticity, tremor, epilepsy,multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease,Alzheimer's disease, epilepsy, Huntington's disease, Tourette'ssyndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma,stroke, spinal cord injury, neuroinflammatory disorders, plaquesclerosis, viral encephalitis, demyelinisation related disorders, aswell as for the treatment of pain disorders, including neuropathic paindisorders, and other diseases involving cannabinoid neurotransmission,including the treatment of septic shock, glaucoma, diabetes, cancer,emesis, nausea, gastrointestinal disorders, gastric ulcers, diarrhoeaand cardiovascular disorders.

[0015] The affinity of the compounds of the invention for cannabinoidCB₁ receptors was determined using membrane preparations of Chinesehamster ovary (CHO) cells in which the human cannabinoid CB, receptor isstably transfected in conjunction with [³H]CP-55,940 as radioligand.After incubation of a freshly prepared cell membrane preparation withthe [³H]-ligand, with or without addition of compounds of the invention,separation of bound and free ligand was performed by filtration overglassfiber filters. Radioactivity on the filter was measured by liquidscintillation counting.

[0016] The cannabinoid CB₁ antagonistic activity of compounds of theinvention was determined by functional studies using CHO cells in whichhuman cannabinoid CB, receptors are stably expressed. Adenylyl cyclasewas stimulated using forskolin and measured by quantifying the amount ofaccumulated cyclic AMP. Concomitant activation of CB, receptors by CB₁receptor agonists (e.g. CP-55,940 or (R)—WIN-55,212-2) can attenuate theforskolin-induced accumulation of cAMP in a concentration-dependentmanner. This CB₁ receptor-mediated response can be antagonized by CB,receptor antagonists such as the compounds of the invention.

[0017] Cannabinoid agonistic of partial agonistic activity of compoundsof the invention can be determined according to published methods, suchas assessment of in vivo cannabimimetic effects (Wiley, J. L. et al., J.Pharmacol. Exp. Ther. 2001, 296, 1013).

[0018] The invention relates both to racemates, mixtures ofdiastereomers and the individual stereoisomers of the compounds havingformula (I).

[0019] The compounds of the invention can be brought into forms suitablefor administration by means of usual processes using auxiliarysubstances and/or liquid or solid carrier materials.

[0020] Suitable synthetic routes for the compounds of the invention arethe following: Synthetic route A

[0021] Step 1: ester hydrolysis of a compound having formula (II)wherein R₇ represents a branched or unbranched alkyl group (C₁₋₄) orbenzyl group

[0022] This reaction gives a compound having formula (III)

[0023] wherein R, R₁ and R₄ have the meanings as described above.

[0024] Intermediates having formula (II), wherein R₇ represents abranched or unbranched alkyl group (C₁₋₄) or benzyl group can beobtained according to methods known, for example:

[0025] a) I. K. Khanna et al., J. Med. Chem. 2000, 43, 3168-3185

[0026] b) N. Kudo et al., Chem. Pharm. Bull. 1999, 47, 857-868

[0027] c) K. Tsuji et al., Chem. Pharm. Bull. 1997, 45, 987-995

[0028] d) I. K. Khanna et al., J. Med. Chem. 1997, 40, 1634-1647

[0029] e) M. Guillemet et al., Tetrahedron Lett. 1995, 36, 547-548

[0030] Step 2: reaction of a compound having formula (III) with acompound having formula R₂R₃NH wherein R₂ and R₃ have the meanings asdescribed above via activating and coupling methods such as formation ofan active ester, or in the presence of a coupling reagent such as DCC,HBTU, BOP or similar reagents. This reaction gives a desired1H-imidazole derivative having formula (I).

[0031] (For more information on activating and coupling methods see: M.Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis,Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7).

[0032] Alternatively, a compound having formula (III) is reacted with ahalogenating agent, for example thionyl chloride (SOCl₂). This reactiongives the corresponding carbonyl chloride (IV).

[0033] Reaction of a compound having formula (IV) with a compound havingformula R₂R₃NH wherein R₂ and R₃ have the meanings as described above,yields a 1H-imidazole derivative having formula (I). This reaction ispreferably carried out in the presence of an organic base such as forexample diisopropylethylamine (DIPEA) or triethylamine.

[0034] Alternatively, a compound having formula (II) is reacted in anamidation reaction with a compound having formula R₂R₃NH wherein R₂ andR₃ have the meanings as described above to give a 1H-imidazolederivative having formula (I).

[0035] Synthetic Route B

[0036] Reaction of a compound having formula (II), wherein R₄ representshydrogen and wherein R, R₁ and R₇ have the meanings as described abovefor compound (II), with a compound having general formula R₄′-X, whereinX represents a leaving group and R₄′ represents a C₁₋₄ alkyl group,which alkyl group may be substituted with 1-3 fluoro atoms or whereinR₄′ represents a cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl,methylsulfanyl or propionyl moiety, or a halogen atom. This reaction iscarried out in the presence of a strong non-nucleophilic base such aslithium diisopropylamide (LDA), preferably under anhydrous conditions inan inert organic solvent, for example tetrahydrofuran, and yields acompound having formula (II)

[0037] wherein R, R₁ and R₇ have the meanings as described hereinaboveand R₄ represents a C₁₋₄ alkyl group, which alkyl group may besubstituted with 1-3 fluoro atoms or wherein R₄ represents a cyano,formyl, acetyl, trifluoroacetyl, fluoroacetyl, methylsulfanyl orpropionyl group, or a halogen atom.

[0038] Compounds of general formula (II) which have been obtainedaccording to synthesis route B can be converted to compounds of generalformula (I) analogously to the procedures described in synthesis routeA, step 1 of route A or step 2 of route A (see above).

[0039] Synthetic Route C

[0040] Compounds having formula (II)

[0041] wherein R₄ represents a branched or unbranched C₁₋₄ alkyl group,which C₁₋₄ alkyl group may be substituted with 1-3 fluoro substituentsand wherein R, R₁ have the meanings given above and R₇ represents abranched or unbranched alkyl group (C₁₋₄) or benzyl group can besynthesized by reacting a compound having formula (V) or its tautomer

[0042] wherein R and R₁ have the meanings given above, with a compoundhaving formula (VI)

[0043] wherein R₄ represents a branched or unbranched C₁₋₄ alkyl group,which C₁₋₄ alkyl group may be substituted with 1-3 fluoro atoms and RBrepresents a leaving group, for example a bromo substituent, and R₇represents a branched or unbranched alkyl group (C₁₋₄) or benzyl group.The reaction is preferably carried out in an organic solvent, forexample in 2-propanol or in N-methyl-2-pyrrolidinone (NMP). The additionof an acid like trifluoroacetic acid (TFA) during the reaction mayenhance the formation of the compounds having formula (II).

[0044] (For more information on the leaving group concept see: M. B.Smith and J. March: Advanced organic chemistry, p. 275, 5^(th) ed.,(2001) John Wiley & Sons, New York, ISBN: 0-471-58589-0).

[0045] Compounds of general formula (II) which have been obtainedaccording to synthesis route C can be converted to compounds of generalformula (I) analogously to the procedures described in synthesis routeA, step 1 of route A or step 2 of route A (see above).

[0046] Compounds of the invention having formula (VI) can be obtainedaccording to methods known, for example: P. Seifert et al., Helv. Chim.Acta, 1950, 33, 725.

[0047] Synthetic Route D

[0048] Reaction of a compound having formula (II)

[0049] wherein R₄ represents a methyl group and R, R₁ have the meaningsgiven above and R₇ represents a branched or unbranched alkyl group(C₁₋₄) or benzyl group with a regioselective brominating compound suchas N-bromo-succinimide (NBS) in an organic solvent such as CCl₄ in thepresence of a free-radical initiator like dibenzoyl peroxide gives acompound of formula (VII)

[0050] wherein R, R₁ and R₇ have the meanings given above. Reaction of acompound having formula (VII) (analogous to the method described inMathews, WB. et al., J. Label. Compds. Radiopharm., 1999, 42, 589) withfor example KCl, KI, KF or KCN gives a compound of formula (VII)

[0051] wherein R, R₁ and R₇ have the meanings given hereinabove and Nurepresents a chloro, iodo, fluoro or cyano group. The reaction ispreferably carried out in the presence of a weak base like NaHCO₃ or inthe presence of a crown ether or a cryptand. (For more information oncrown ethers and cryptands see: M. B. Smith and J. March: Advancedorganic chemistry, p. 105, 5^(th) ed., (2001) John Wiley & Sons, NewYork, ISBN: 0-471-58589-0).

[0052] Compounds of general formula (VII) or (VIII) which have beenobtained according to synthesis route D can be converted to compounds ofgeneral formula (I) analogously to the procedures described in synthesisroute A, step 1 of route A, or step 2 of route A (see above).

EXAMPLE 1

[0053] Part A: To a 1M solution of sodium bis(trimethylsilyl) amide inTHF (70 mL) is added dropwise a solution of 4-chloroaniline (8.86 gram,69.5 mmol) in anhydrous THF in a nitrogen atmosphere. After the mixtureis stirred for 20 minutes a solution of 2,4-dichlorobenzonitrile (12gram, 70 mmol) in THF is added. The resulting mixture is stirredovernight, poured into ice-water (400 mL) and extracted withdichloromethane, dried over Na₂SO₄ and concentrated in vacuo to give ayellow oil (15.7 gram). Crystallisation from a dichloromethane/heptanemixture, and subsequent washing with methyl-t-butyl ether givesN-(4-chlorophenyl)-2,4-dichlorobenzenecarboxamidine (8.66 gram, 42%yield) as a yellow solid. Melting point (MP): 93-95° C.

[0054] Analogously was prepared:

[0055] N-(4-bromophenyl)-2,4-dichlorobenzenecarboxamidine. MP: 117-119°C.

[0056] Part B: A mixture ofN-(4-chlorophenyl)-2,4-dichlorobenzenecarboxamidine (2.00 gram, 6.68mmol), ethyl 3-bromo-2-oxopropanoate (2.65 gram, 13.6 mmol) and NaHCO₃(1.12 gram, 13.3 mmol) in 2-propanol is stirred at reflux temperaturefor 20 hours. After cooling to room temperature the mixture isconcentrated in vacuo and the residue suspended in dichloromethane,washed with water (3×50 mL) and brine (3×50 mL). The aqueous layers areextracted with dichloromethane. The combined organic layers are driedover Na₂SO₄ and concentrated in vacuo to afford crude brown product (2.0gram). This product is further purified by column chromatography(silicagel, heptane/EtOAc=90/10 (v/v)) to yield ethyl1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate(0.759 gram, 29% yield) as a yellow oil which slowly solidifies onstanding. Melting point: 150-152° C.; MS: 395 (MH⁺). ¹H-NMR (400 MHz,CDCl₃): δ 7.91 (s, 1H), 7.49 (dd, J=8 Hz, J=2 Hz, 1H), 7.29-7.36 (m,4H), 7.07 (dt, J=8 Hz, J=2 Hz, 2H), 4.44 (q, J=7 Hz, 2H), 1.42 (t, J=7Hz, 3H).

[0057] Part C: Ethyl1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate(0.810 gram, 2.06 mmol) and LiOH (0.173 g, 7.20 mmol) are dissolved in aH₂O/THF (20 mL/20 mL) mixture and stirred at 50° C. for 16 hours. Themixture is concentrated in vacuo to give1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylicacid. Thionyl chloride (60 mL) is added and the mixture is heated atreflux temperature for 1 hour and concentrated in vacuo to give crude1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carbonylchloride.

[0058] Part D: Crude1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carbonylchloride (919 mg, 2.39 mmol), 1-aminopiperidine (0.469 g, 4.69 mmol) andtriethylamine (0.363 g, 3.59 mmol) are dissolved in dichloromethane andstirred for one hour at room temperature. The mixture is washed with asaturated aqueous NaHCO₃ solution (3×20 mL), dried over Na₂SO₄ andconcentrated in vacuo and further purified by column chromatography(ethyl acetate, silicagel) to give1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide(356 mg, 26% yield (based on ethyl1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate).Mass Spectrometry (MS): 449.

[0059] Analogously were prepared:

[0060] 2.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1H-imidazole-4-carboxamide;MS: 435.

[0061] 3.N-(t-Butoxy)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide;MS: 438.

[0062] 4.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-phenyl-1H-imidazole-4-carboxamide;MS: 442.

[0063] 5.1-(4-Chlorophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide;MS: 448.

[0064] 6.N-(Benzyl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-1H-imidazole-4-carboxamide;MS: 470.

[0065] 7.1-[1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-4-(1H-imidazolyl)carbonyl]hexahydro-1H-azepine; MS: 448.

[0066] 8.2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide(prepared from 2,4-dichloroaniline and 4-chlorobenzo-nitrile); MS: 449.

[0067] 9.N-(t-Butoxy)-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide(prepared from 2,4-dichloroaniline and 4-chlorobenzonitrile); MS: 438.

Example 10

[0068] Part A: Diisopropylamine (2.30 gram, 22.8 mmol) is added dropwiseto anhydrous THF (100 mL) in a nitrogen atmosphere at 0° C. n-BuLi isadded dropwise (7.34 mL, 2.5 M solution in hexane, 18.4 mmol). Theresulting solution is cooled to −78° C. A solution of ethyl2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate(6.0 gram, 15.2 mmol) in anhydrous THF is added dropwise. The colour ofthe mixture changes from yellow to purple brown. The stirred mixture iswarmed to −40° C. and cooled to −78° C. and allowed to stand for 30minutes. Methyl iodide (6.44 gram, 45.4 mmol) is added dropwise and theresulting solution is stirred for 30 min at −78° C. and then allowed toattain room temperature. The resulting solution is quenched with anaqueous NH₄Cl solution, diethyl ether is added and the organic layer isdried over MgSO₄, filtered and concentrated in vacuo to give an oil (6.4gram). This oil is purified by column chromatography (toluene/EtOAc=10/2(v/v), silicagel) to give pure ethyl2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate(5.3 gram, 85% yield) as a yellow oil.

[0069] Part B: Ethyl2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate(0.250 gram, 0.61 mmol) and LiOH (0.052 gram, 2.17 mmol) are dissolvedin H₂O/THF (1:1 (v/v); 50 mL) and stirred at 50° C. for one hour. Themixture is concentrated to give crude2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylicacid. To this mixture is added SOCl₂ (50 mL) and the resulting mixtureis heated at reflux temperature for 1 hour. The mixture is concentratedto give2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carbonylchloride.

[0070] Part C:2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole4-carbonylchloride (1.5 gram, 3.75 mmol), 1-aminopiperidine (0.725 gram, 7.25mmol) and triethylamine (0.549 gram, 5.44 mmol) are dissolved indichloromethane and stirred for one hour at room temperature. Themixture is washed with a saturated aqueous NaHCO₃ solution, dried overNa₂SO₄ and concentrated in vacuo and further purified by columnchromatography (heptane/ethyl acetate=1/1 (v/v), silicagel) to give2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide(0.220 gram, 13% yield) as a white foam. MS: 463.

[0071] Analogously were prepared:

[0072] 11.N-(t-Butoxy)-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide:MS: 452.

[0073]12.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide:MS: 463; Melting point: 165-167° C.

[0074] 13.N-(t-Butoxy)-2-(2,4-dichlorophenyl)-1-(4-chlorophenyl)-5-methyl-1H-imidazole-4-carboxamide:MS: 452.

[0075] 14.N-(t-Butoxy)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazole4-carboxamide:Amorphous. MS: 468.

[0076] 15.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide:MS: 477.

[0077] 16.1-(4-Bromophenyl)-N-(t-butoxy)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide:Amorphous.

[0078] 17.1-(4-Bromophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide:MP: >204° C. TLC (Silicagel, EtOAc) R_(f)=0.3.

[0079] 18.1-(4-Bromophenyl)-N-(t-butoxy)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazole-4-carboxamide:Amorphous. TLC (Silicagel, CH₂Cl₂/acetone=9/1 (v/v)) R_(f)=0.45.

[0080] 19.1-(4-Bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide:MP: >140° C. TLC (Silicagel, EtOAc) R_(f)=0.4.

[0081] 20.1-(4-Bromophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazole-4-carboxamide:Melting point>135-140° C.

[0082] 21.1-(4-Bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(n-pentyl)-1H-imidazole-4-carboxamide:Syrup. TLC (Silicagel, CH₂Cl₂/acetone=19/1 (v/v)) R_(f)=0.4.

Example 22

[0083] Part A: To a stirred solution of ethyl1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate(6.10 gram, 0.0139 mol) in THF (70 mL) is added LiOH (0.67 gram, 0.0278mol) and water (70 mL). The resulting mixture is stirred for 16 hours at50° C. to give a clear solution. After cooling to room temperature, HCl(1 N solution, 28 mL) is added to give an oily precipitate whichcompletely solidifies on continued stirring and addition of water (70mL). The precipitate is collected by filtration, washed with water anddried in vacuo to give1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid(4.92 gram, 86% yield). Melting point: 138-142° C.

[0084] Part B: To a stirred suspension of1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid(1.23 gram, 2.99 mmol) in dry acetonitrile (40 mL) is successively addeddiisopropylethylamine (DIPEA) (1.15 mL, 6.6 mmol),O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexafluorophos-phate(HBTU) (1.36 gram, 3.6 mmol) and 1-aminopiperidine (0.39 mL, 3.6 mmol).After stirring for 16 hours, the resulting mixture is concentrated invacuo. The residue is dissolved in ethylacetate and an aqueous NaHCO₃solution is added. The ethylacetate layer is collected, washed withwater and brine, dried over Na₂SO₄, filtered and concentrated in vacuoto give a crude solid. This solid is further purified byrecrystallisation from acetonitrile to give1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide(830 mg, 56% yield). Melting point: 219-221° C.

[0085] Analogously were prepared:

[0086] 23.N-(t-Butoxy)-1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide.Amorphous. TLC (Silicagel, Et₂O)R_(f)=0.3.

[0087]24.1-(4-Bromophenyl)-2-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 238-240° C.

[0088] 25.N-(Azepan-1-yl)-1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 201-204° C.

[0089] 26.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(hexahydrocyclopentatclpyrrol2(1H)-yl)-1H-imidazole-4-carboxamide. MS: 475.

[0090]27.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(4-fluorobenzyl)-1H-imidazole-4-carboxamide.MS: 474.

[0091]28.1-(4-Chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 220° C.

[0092] 29.1-(4-Chlorophenyl)-N-cyclohexyl-2-(2-methoxy-4-chlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 177-179° C.

[0093] 30.1-(4-Chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 217-218° C.

[0094] 31.2-(2,4-Dichlorophenyl)-1-(4-fluorophenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 175-176° C.

[0095] 32.N-Cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-1H-imidazole-4-carboxamide.Melting point: 184-185° C.

[0096] 33.N-Cyclohexyl-2-(2-fluoro-4-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 157-159° C.

[0097] 34.1-(4-Chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-N-(n-penty!)-1H-imidazole-4-carboxamide.Melting point: 115° C.

[0098] 35.2-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 178-179° C.

[0099] 36.N-Cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide.Melting point: 175-176° C.

[0100] 37.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N,N-diethyl-1H-imidazole-4-carboxamide.Melting point: 177-179° C.

[0101] 38.1-(4-Chlorophenyl)-N-cyclohexyl-2-(2-trifluoromethyl4-chlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 172° C.

[0102] 39.1-(4-Chlorophenyl)-N-(piperidin-1-yl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 219° C.

[0103] 40.N-(1-Adamantyl)-1-(4-chlorophenyl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 288° C.

[0104] 41.1-(4-Chlorophenyl)-N-(2,2,2-trifluoroethyl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 149° C.

[0105] 42.2-(2,4-Dichlorophenyl)-1-(pyridin-3-yl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 165-170° C.

[0106] 43.N-Cyclohexyl-2-(2,4-dichlorophenyl)-1-(pyridin-3-yl)-1H-imidazole-4-carboxamide.Melting point: 195° C.

[0107] 44.2-(2,4-Dichlorophenyl)-1-(pyridin-3-yl)-N-(n-pentyl)-1H-imidazole-4-carboxamide.

[0108] Melting point: 117° C.

Example 45

[0109] Part A: 2,4-Dichlorobenzoyl chloride (40.0 g, 0.19 mol) isdissolved in tetrahydrofuran (1 L). To the resulting stirred solution issuccessively added diisopropylethylamine (DIPEA) (73.4 mL, 2.2 molarequivalent) and 4-(trifluoromethyl)phenylamine (30.7 g, 0.19 mol). Afterone hour the mixture is concentrated in vacuo to give an oil. This oilis crystallised from ethanol to give pure2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (53.2 g, 83% yield).¹H-NMR (200 MHz, DMSO-d₆): δ 10.90 (br s, 1H), 7.91 (br d, J=8 Hz, 2H),7.63-7.77 (m, 4H), 7.57 (dt, J=8 Hz, J=2 Hz, 1H).

[0110] Part B: 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (19.0g, 0.057 mol) is dissolved in benzene (150 mL) and PCI₅ (13.0 g, 1.1molar equivalent) is added. The resulting mixture is heated at refluxtemperature for two hours, allowed to attain room temperature andconcentrated in vacuo to give a residue. The residue is dissolved inanhydrous THF, cooled to 0° C. and transferred into an autoclave. ExcessNH₃ is quickly added from a lecture bottle and the mixture is stirred atroom temperature for 50 hours. A mixture of ethylacetate and aqueousNaHCO₃ is added. The ethylacetate layer is collected, dried over Na₂SO₄,filtered and concentrated in vacuo. The resulting oil is purified bycolumn chromatography (diethyl ether/petroleum ether=1/1 (v/v),silicagel) to give pure2,4-dichloro-N-(4-(trifuoromethyl)phenyl)benzene-carboxamidine (16.9 g,89% yield). Melting point: 108-109° C.

[0111] Part C:2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzenecarboxamidine (15.0 g,0.0450 mol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate(20.8 g, 2 molar equivalent) and NaHCO₃ are successively added. Theresulting mixture is heated at reflux temperature for 40 hours andallowed to attain room temperature. The 2-propanol is removed in vacuo,ethyl acetate is added to the residue and the resulting organic layer iswashed with NaHCO₃ (5% aqueous solution). The ethylacetate layer iscollected, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting oil is purified by column chromatography (diethylether/petroleum ether=1/3 (v/v), silicagel) and further purified bycrystallisation from cyclohexane to give ethyl2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole4-carboxylate(10.45 g, 52% yield) as a yellow solid. Melting point: 160-162° C.

[0112] Part D: The formed ethyl2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylate is converted to2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylicacid (melting point: 224-226° C.), which carboxylic acid is converted to2-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide(melting point: 173-174° C.) according to the procedure described inexample 22 above.

[0113] Analogously were prepared

[0114] 46.2-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide.Melting point: >200° C. (decomposition).

[0115] 47.N-Cyclohexyl-2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide. Melting point: 178-179° C.

[0116] 48.N-Cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide.Melting point: 199-200° C.

Example 49

[0117] Part A: N-(4-methoxyphenyl)-2,4-dichlorobenzenecarboxamidine(15.0 gram, 50.8 mmol) is dissolved in 2-propanol and ethyl3-bromo-2-oxobutanoate (23.5 g, 2 molar equivalents) and NaHCO₃ (8.5gram, 2 molar equivalents) are successively added.

[0118] The resulting mixture is heated at reflux temperature for 40hours and allowed to attain room temperature. The 2-propanol is removedin vacuo, ethyl acetate is added to the residue and the resultingorganic layer is washed with NaHCO₃ (5% aqueous solution). Theethylacetate layer is collected, dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting oil is purified by columnchromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) togive ethyl2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxy-phenyl)-1H-imidazole-4-carboxylate(8.61 g, 42% yield) as a solid. ¹H-NMR (200 MHz, CDCl₃): δ 7.33 (d, J=8Hz, 1H), 7.27 (d, J=2 Hz, 1H), 7.18 (dd, J=8 Hz, J=2 Hz, 1H), 7.03 (dt,J=8 Hz, J=2 Hz, 2H), 6.85 (dt, J=8 Hz, J=2 Hz, 2H), 4.42 (q, J=7 Hz,2H), 3.80 (s, 3H), 2.43 (s, 3H), 1.43 (t, J=7 Hz, 3H).

[0119] Part B: To a stirred solution of ethyl2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole4-carboxylate(8.00 gram, 0.0198 mol) in THF (80 mL) is added LiOH (0.59 gram, 2 molarequivalents) and water (80 mL). The resulting mixture is stirred for 16hours at 80° C. After cooling to room temperature, HCl (2N solution,12.3 mL) is added to give an oily precipitate. After addition of waterand extraction with ethylacetate, the ethylacetate layer is collected,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue iscrystallised from diisopropyl ether and dried to give2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylicacid (4.04 gram, 87% yield) as a pale grey solid. Melting point:189-191° c.

[0120] Part C: To2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylicacid (1.00 gram, 2.65 mmol) in dry acetonitrile (25 mL) is successivelyadded diisopropylethylamine (DIPEA) (1.02 mL, 2.2 molar equivalents),O-benzotriazol-1-yl-N,N, N′,N′-tetramethyluronium hexafluoro-phosphate(HBTU) (1.21 gram, 1.2 molar equivalents) and the resulting solution isstirred for 15 minutes. Cyclohexylamine (0.36 mL, 1.2 molar equivalents)is added. After stirring for 50 hours, the resulting mixture isconcentrated in vacuo. The residue is dissolved in dichloromethane andan aqueous NaHCO₃ solution is added. The dichloromethane layer iscollected, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue is further purified by column chromatography (gradient:dichloromethane=>dichloromethane/methanol=99/1 (v/v), silicagel) to giveN-(1-cyclohexyl)-2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole4-carboxamide(1.03 gram, 85% yield). Melting point: 160-161° C.

[0121] Analogously were prepared:

[0122] 50.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N,N,5-trimethyl-1H-imidazole-4-carboxamide.Melting point: 101-104° C.

[0123] 51.1-(4-dichloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.MS: 464 (MH⁺).

[0124]52.1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(4-morpholinyl)-1H-imidazole-4-carboxamide.MS: 466 (MH⁺).

[0125] 53.N-(1-Azepanyl)-1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.MS: 478 (MH⁺).

[0126] 54.1-(4-Chloropyridin-2-yl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.MS: 463.

[0127] 55.1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazole-4-carboxamide.MS: 451.

[0128] 56.1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-N-(4-fluorobenzyl)-5-methyl-H-imidazole-4-carboxamide.MS: 489. Melting point: 123-126° C.

[0129] 57.1-(4-Chlorophenyl)-N-cyclohexyl-5-methyl-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 212° C.

[0130] 58.1-(4-Chlorophenyl)-5-methyl-N-(piperidin-1-yl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 165° C.

[0131] 59.1-(4-Chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazole-4-carboxamide.Melting point: 131° C.

[0132] 60.1-(4-Chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: >256° C.

[0133] 61.N-Cyclohexyl-1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 201° C.

[0134] 62.2-(2,4-Dichlorophenyl)-1-(4-fluorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 223-224° C.

[0135] 63.2-(2,4-Dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: >90° C. (decomposition).

[0136] 64.N-Cyclohexyl-1-(4-fluorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 229-230° C.

[0137] 65.1-(4-Chlorophenyl)-5-methyl-N-(n-pentyl)-2-(2-trfluoromethyl4-chlorophenyl)-1H-imidazole-4-carboxamide.Amorphous.

[0138] 66.1-(4-Chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 195° C.

[0139] 67.1-(4-Chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazole-4-carboxamide.Melting point: 115° C.

[0140] 68.1-(4-Chlorophenyl)-N-(cyclohexyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 188° C.

[0141] 69.1-(4-Chlorophenyl)-N-(cyclohexyl)-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 188-189° C.

[0142] 70.1-(4-Chlorophenyl)-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 208-210° C.

[0143] 71.2-(2-Chlorophenyl)-1-(3-fluorophenyl)-5-methyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 236-238° C.

[0144] 72.2-(2-Chlorophenyl)-1-(3-fluorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazole-4-carboxamide.Melting point: 97-102° C.

[0145] 73.2-(2-Chlorophenyl)-N-cyclohexyl-1-(3-fluorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 180-182.5° C.

[0146] 74.2-(2-Chlorophenyl)-1-(3-fluorophenyl)-N-(2-(4-fluorophenyl)ethyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 123.5-126° C.

[0147] 75.1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 146° C.

[0148] 76.1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(4-morpholinyl)-1H-imidazole-4-carboxamide.Melting point: 223° C.

[0149] 77.N-(1-Azepanyl)-1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazole-4-carboxamide.Melting point: 177° C.

[0150] 78.1-(4-Chloropyridin-2-yl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazole-4-carboxamide.Melting point: 149° C.

[0151] 79.1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(n-pentyl)-1H-imidazole-4-carboxamide.Melting point: Oil.

[0152] 80.1-(4-Chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(4-fluorophenylmethyl)-1H-imidazole-4-carboxamide.MP: amorphous.

[0153] 81.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(hexahydrocyclopenta-[c]pyrrol-2(1H)-yl)-5-methyl-1H-imidazole-4-carboxamide.MP: 143-146° C.

[0154] 82.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-phenyl-1H-imidazole-4-carboxamide.Melting point: 91-95° C.

[0155] 83.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(tetrahydro-2H-pyran-2-yloxy)-1H-imidazole-4-carboxamide.Melting point: 128-133° C.

[0156] 84.N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 194-195° C.

[0157] 85.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-fluoroethyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 128-133° C.

[0158] 86.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(trans-4-hydroxycyclohexyl)-5-methyl-1H-imidazole4-carboxamide.Melting point: 160° C. (dec.).

[0159] 87.1-{[1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-yl]carbonyl}-4-hydroxypiperidine.Melting point: Amorphous.

[0160] 88.1-{[1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-yl]carbonyl}1,2,3,4-tetrahydroisoquinoline.Melting point: 143-146° C.

[0161] 89.N-(Endo-bicyclo[2.2.1]hept-2-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 194-195° C.

[0162] 90.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-N-(4-fluorobenzyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 165-166° C.

[0163] 91.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazole-4-carboxamide.Oil.

[0164] 92.N-(Azepan-1-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 147-149° C.

[0165] 93.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(pyrrolidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 205-206° C.

[0166] 94.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(morpholin-4-yl)-1H-imidazole-4-carboxamide.Melting point: 225° C. (dec.).

[0167] 95.2-(2,5-Dichlorophenyl)-5-methyl-1-phenyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 227° C.

[0168] 96.N-Cyclohexyl-2-(2,5-dichlorophenyl)-5-methyl-1-phenyl-1H-imidazole-4-carboxamide.Melting point: 236° C.

[0169] 97.N-Cyclohexyl-2-(2,4-dichlorophenyl)-1-(2,5-difluorophenyl)-5-ethyl-1H-imidazole-4-carboxamide.Melting point: 144-146° C.

[0170] 98.N-Cyclohexyl-2-(2,4-dichlorophenyl)-1-(2,5-difluorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 206-208° C.

[0171] 99.N-Cyclohexyl-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-ethyl-1-phenyl-1H-imidazole-4-carboxamide.Melting point: 195-196° C.

[0172] 100.N-Cyclohexyl-2-(2,5-dichlorophenyl)-5-ethyl-1-phenyl-1H-imidazole-4-carboxamide.Melting point: 198-199° C.

[0173] 101.2-(2,5-Dichlorophenyl)-5-ethyl-1-phenyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 207-208° C.

[0174] 102.1-(4-Chlorophenyl)-5-methyl-2-(3-methylpyridin-2-yl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 211-213° C.

[0175]103.1-(4-Chlorophenyl)-N-cyclohexyl-5-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole4-carboxamide.Melting point: 188-190° C.

[0176] 104.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxamide.Melting point: 177° C.

[0177] 105.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(3-(trifluoromethyl)benzyl)-1H-imidazole-4-carboxamide.Melting point: 138-140° C.

[0178] 106.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(4-(trifluoromethyl)benzyl)-1H-imidazole-4-carboxamide.Melting point: 232° C.

[0179] 107.1-(4-Chlorophenyl)-N-cyclopentyl-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 172° C.

[0180] 108.1-(4-Chlorophenyl)-N-cycloheptyl-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide.Melting point: 154-156° C.

Example 109

[0181] Part A: Ethyl1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate isconverted to ethyl1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylateanalogously to a published procedure (N. Kudo et al., Chem. Pharm. Bull.1999, 47, 857-868) using excess of SO₂Cl₂ in dichloroethane at refluxtemperature for 50 hours.

[0182] Part B: Ethyl1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylateis converted to1-(4-bromophenyl)-5-chloro-2-(2,4-dichloro-phenyl)-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide(melting point: >150° C.; Rf (Silicagel, EtOAc) 0.35) analogously to theprocedure described in example 22 above. ¹H-NMR (400 MHz, CDCl₃): δ 7.85(br s, 1H), 7.52 (dt, J=8 Hz, J=2 Hz, 2H), 7.26-7.36 (m, 3H), 7.01 (dt,J=8 Hz, J=2 Hz, 2H), 2.85-2.92 (m, 4H), 1.72-1.80 (m, 4H), 1.40-1.44 (m,2H).

Example 110

[0183] Part A: To a stirred solution of1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid(18.38 gram, 50 mmol) in toluene (200 mL) in a nitrogen atmosphere isadded N,N-dimethylformamide di-tert-butyl acetal (50 mL) and theresulting mixture is heated at 80° C. for 4 hours. After cooling to roomtemperature the reaction mixture is concentrated and diethyl ether isadded. The resulting solution is twice washed with water, dried overMgSO₄, filtered and concentrated in vacuo. The residue is crystallisedfrom diisopropyl ether to give pure tert-butyl1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate(10.35 gram, 49% yield). Melting point: 179-181° C.

[0184] Part B:

[0185] Lithium diisopropyl amide (LDA) (5.25 mL of a 2 M solution inTHF, 0.0105 mol) is added dropwise to a cooled solution (−70° C.) oftert-butyl1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate(4.24 gram, 0.010 mol) in anhydrous THF (80 mL) in a nitrogen atmosphereand the resulting mixture is stirred for one hour. A solution ofp-toluenesulfonyl cyanide (1.88 gram, 0.011 mol) in anhydrous THF (20mL) is added dropwise and the resulting red solution is stirred for onehour at −70° C. and then allowed to attain room temperature. Diethylether is added and the resulting solution is quenched with water andfiltered over hyflo. The organic layer is collected and washed withwater, dried over MgSO₄, filtered and concentrated in vacuo to give anoil. This oil is purified by column chromatography (dichloromethane,silicagel) to give 3.4 gram of tert-butyl1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole4-carboxylate.Recrystallisation from diisopropyl ether gave crystalline tert-butyl1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole4-carboxylate(2.57 gram, 57% yield). Melting point: 210-212° C.

[0186] Analogously was prepared:

[0187] Tert-butyl1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate.¹H-NMR (400 MHz, CDCl₃): δ 7.38 (d, J=8 Hz, 1H), 7.34 (dt, J=8 Hz, J=2Hz, 2H), 7.27 (d, J=2 Hz, 1H), 7.22 (dd, J=8 Hz, J=2 Hz, 1H), 7.03 (dt,J=8 Hz, J=2 Hz, 2H), 2.40 (s, 3H), 1.63 (s, 9H).

[0188] Part C:

[0189] To a solution of tert-butyl1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-cyano-1H-imidazole-4-carboxylate(2.57 gram, 5.73 mmol) in dichloromethane (40 mL) is addedtrifluoroacetic acid and the resulting solution is stirred at roomtemperature for 20 hours and concentrated in vacuo. The residue iscrystallised from diisopropyl ether to give pure1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylicacid (1.95 gram, 87% yield). Melting point: 200-202° C. (dec.).

[0190] Part D:

[0191]1-(4-Chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylicacid is converted to1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-N-(piperldin-1-yl)-1H-imidazole-4-carboxamidein 60% yield, analogously to the procedure described in example 22, partB herein above. Melting point: 231-233.5° C.

[0192] Analogously were prepared:

[0193] 111.1-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-5-iodo-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide.Melting point: 196-201° C.

[0194] 112.1-(4-Chlorophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-iodo-1H-imidazole-4-carboxamide.Melting point: 226-230° C.

[0195] 113.1-(4-Chlorophenyl)-5-cyano-N-cyclohexyl-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxamide.Melting point: 157-158° C.

1. A compound of formula (I)

wherein R represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, whichgroups may be substituted with 1, 2, 3 or 4 substituents Y, which can bethe same or different, from the group C₁₋₃-alkyl or alkoxy, hydroxy,halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro,amino, mono- or dialkyl (C₁₋₂)-amino, mono- or dialkyl (C₁₂)-amido,(C₁₋₄)-alkoxycarbonyl, carboxyl, cyano, carbamoyl and acetyl, or Rrepresents naphtyl, with the proviso that when R is 4-pyridinyl, R₄represents a halogen atom or a cyano, carbamoyl, formyl, acetyl,trifluoroacetyl, fluoroacetyl, propionyl, sulfamoyl, methanesulfonyl,methylsulfanyl or branched or unbranched C₁₋₄ alkyl group, which C₁₋₄alkyl group may be substituted with 1-3 fluoro atoms or with a bromo,chloro, iodo, cyano or hydroxy group, R₁ represents phenyl or pyridinyl,which groups may be substituted with 14 substituents Y, which can be thesame or different, wherein Y has the above mentioned meaning, or R₁represents pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, whichgroups may be substituted with 1-2 substituents Y, which can be the sameor different or R₁ represents a five-membered aromatic heterocyclic ringhaving one or two heteroatoms from the group (N, O, S), whichheteroatoms can be the same or different, which five-membered aromaticheterocyclic ring may be substituted with 1-2 substituents Y, which canbe the same or different or R₁ represents naphtyl, R₂ represents H,branched or unbranched C₁₋₈ alkyl, C₃₋₈ cycloalkyl, Cm alkenyl, C₅₋₈cycloalkenyl which groups may contain a sulfur, oxygen or nitrogen atom,R₃ represents branched or unbranched C₂₋₈ alkyl, C₁ alkoxy, C₅₋₈cycloalkyloxy, C₃₋₈ cycloalkyl, C₅₋₁₀ bicycloalkyl, C₆₋₁₀ tricycloalkyl,C₃₋₈ alkenyl, C₅₋₈ cycloalkenyl, which groups may optionally contain oneor more heteroatoms from the group (O, N, S) and which groups may besubstituted with a hydroxy group or 1-2 C₁₋₃ alkyl groups or 1-3 fluoroatoms, or R₃ represents a benzyl or phenethyl group which aromatic ringsmay be substituted with 1-5 substituents Z, which can be the same ordifferent, from the group C₁₋₃-alkyl or alkoxy, hydroxy, halogen,trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino,mono- or dialkyl (C₁₂)-amino, mono- or dialkyl (C₁₋₂)-amido,(C₁₋₃)-alkylsulfonyl, dimethyl-sulfamido, C₁₋₃-alkoxycarbonyl, carboxyl,trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R₃represents a phenyl or pyridinyl group, which groups are substitutedwith 1-4 substituents Z, wherein Z has the meaning as indicated above,or R₃ represents a pyridinyl group, or R₃ represents a phenyl group,with the proviso that R₄ represents a halogen atom or a cyano,carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl, propionyl,sulfamoyl methanesulfonyl, methylsulfanyl or C₁₋₄ alkyl group, whichC₁₋₄ alkyl group may be substituted with 1-3 fluoro atoms or with abromo, chloro, iodo, cyano or hydroxy group, or R₃ represents a groupNR₅R₆ with the proviso that R₂ represents a hydrogen atom or a methylgroup, wherein R₅ and R₆ are the same or different and representbranched or unbranched C₁₋₄ alkyl, or R₅ and R₆— together with thenitrogen atom to which they are bonded—form a saturated or unsaturated,monocyclic or bicyclic heterocyclic group having 4 to 10 ring atomswhich heterocyclic group contains one or two heteroatoms from the group(N, O, S), which heteroatoms can be the same or different, whichheterocyclic group may be substituted with a C₁₋₃ alkyl group or ahydroxy group, or R₂ and R₃— together with the nitrogen atom to whichthey are bonded—form a saturated or unsaturated heterocyclic grouphaving 4 to 10 ring atoms which heterocyclic group contains one or twoheteroatoms from the group (N, O, S), which heteroatoms can be the sameor different, which heterocyclic group may be substituted with a C₁₋₃alkyl group or a hydroxy group, R₄ represents a hydrogen or halogen atomor a cyano, carbamoyl, formyl, acetyl, trifluoroacetyl, fluoroacetyl,propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or branched orunbranched C₁₋₄ alkyl group, which C₁₋₄ alkyl group may be substitutedwith 1-3 fluoro atoms or with a bromo, chloro, iodo, cyano or a hydroxygroup, and prodrugs, stereoisomers and salts thereof.
 2. Pharmaceuticalcompositions containing a pharmacologically active amount of at leastone compound as claimed in 1 as an active component.
 3. Method ofpreparing pharmaceutical compositions as claimed in claim 2characterised in that a compound as claimed in claim 1 is brought in aform suitable for administration.
 4. Process for the preparation ofcompounds having formula (I), characterised in that a compound isprepared wherein R, R₁-R₃ have the meanings given in claim 1 and R₄represents a hydrogen or halogen atom or a cyano, carbamoyl, formyl,acetyl, trifluoroacetyl, propionyl, sulfamoyl, methanesulfonyl,methylsulfanyl or C₁₋₄ alkyl group, which C₁₋₄ alkyl group may besubstituted with 1-3 fluoro atoms, by reacting a compound having formula(II), (Ill) or (IV) with a compound of formula R₂R₃NH.
 5. Process forthe preparation of compounds having formula (Ii)

wherein R₄ represents a C₁₋₄ alkyl group, which C₁₋₄ alkyl group may besubstituted with 1-3 fluoro substituents, or wherein R₄ represents ahalogen atom or a cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl,methylsulfanyl or propionyl group, characterized in that a compound isprepared wherein R and R₁ have the meanings given in claim 1 and R₇represents a branched or unbranched alkyl group (C₁₋₄) or benzyl group,by reacting a compound having formula (II) wherein R₄ is a hydrogen atomwith a compound having formula R₄′-X, wherein X represents a leavinggroup and R₄′ represents a C₁₋₄ alkyl group, which C₁₋₄ alkyl group maybe substituted with 1-3 fluoro substituents, or wherein R₄′ represents ahalogen atom or a cyano, formyl, acetyl, trifluoroacetyl, fluoroacetyl,methylsulfanyl or propionyl group, in the presence of a strongnon-nucleophilic base.
 6. Process for the preparation of a compoundhaving formula (II)

wherein R₄ represents a branched or unbranched C₁₋₄ alkyl group, whichC₁₋₄ alkyl group may be substituted with 1-3 fluoro substituents,characterized in that a compound is prepared wherein R, R₁ have themeanings given in claim 1 and R₇ represents a branched or unbranchedalkyl group (C₁₄) or benzyl group, by reacting a compound having formula(V) or its tautomer

wherein R and R₁ have the meanings given in claim 1, with a compoundhaving formula (VI)

wherein R₄ represents a branched or unbranched C₁₋₄ alkyl group, whichC₁₋₄ alkyl group may be substituted with 1-3 fluoro atoms and R₈represents a so-called leaving group and R₇ represents a branched orunbranched alkyl group (C₁₋₄) or benzyl group.
 7. Compounds of formula(IX)

wherein R and R₄ have the meanings given in claim 1 and wherein R₁represents a phenyl or pyridinyl group, which groups are substitutedwith 14 substituents Y, which can be the same or different, or R₁represents a pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl group,which groups are substituted with 1-2 substituents Y, which can be thesame or different or R₁ represents a five-membered aromatic heterocyclicmoiety having one or two heteroatoms from the group (N, O, S), whichheteroatoms can be the same or different, which five-membered aromaticheterocyclic moiety may be substituted with 1-2 substituents Y, whichcan be the same or different or R₁ represents naphtyl and R₉ representsa hydroxy group, a branched or unbranched alkoxy (C₁₄) group, abenzyloxy group or a chloro substituent.
 8. Compounds of formula (X) andtautomers thereof.

wherein R represents a 4-chlorophenyl group, a. 4-bromophenyl group or a4-(trifluoromethyl)phenyl group.
 9. Use of a compound as claimed inclaim 1 for the preparation of a pharmaceutical composition for thetreatment of disorders involving cannabinoid neurotransmission.
 10. Useas claimed in claim 9 characterised in that said disorders arepsychiatric disorders such as psychosis, anxiety, depression, attentiondeficits, memory disorders, cognitive disorders, appetite disorders,obesity, addiction, appetence, drug dependence and neurologicaldisorders such as neurodegenerative disorders, dementia, dystonia,muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic braininjury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy,Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebralapoplexy, craniocerebral trauma, stroke, spinal cord injury,neuroinflammatory disorders, plaque sclerosis, viral encephalitis,demyelinisation related disorders, as well as for the treatment of paindisorders, including neuropathic pain disorders, and other diseasesinvolving cannabinoid neurotransmission, including the treatment ofseptic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma,respiratory diseases, gastrointestinal disorders, gastric ulcers,diarrhoea and cardiovascular disorders.